Clinical translation of controlled protein delivery systems for tissue engineering

Abstract

Strategies that utilize controlled release of drugs and proteins for tissue engineering have enormous potential to regenerate damaged organs and tissues. The multiple advantages of controlled release strategies merit overcoming the significant challenges to translation, including high costs and long, difficult regulatory pathways. This review highlights the potential of controlled release of proteins for tissue engineering and regenerative medicine. We specifically discuss treatment modalities that have reached preclinical and clinical trials, with emphasis on controlled release systems for bone tissue engineering, the most advanced application with several products already in clinic. Possible strategies to address translational and regulatory concerns are also discussed.

Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds

“…Protein delivery strategies that are designed to cause vascularization following implantation in vivo include scaffolds that sequentially release pro-angiogenic factors like VEGF followed by pro-maturation factors like PDGF-BB [10, 29]. The regulation of blood vessels is a complex process involving a myriad of growth factors and signaling molecules released at precise timing and doses [30], making recapitulation with synthetic drug delivery systems an impossible task.…”

“…This process is tightly regulated by a series of angiogenic growth factors, especially vascular endothelial growth factor (VEGF) and platelet-derived growth factor-BB (PDGF-BB), which act in a sequential fashion to stimulate and stabilize blood vessel growth, respectively [5, 8]. The sequential application of growth factors following this natural temporally defined sequence of VEGF and PDGF-BB in angiogenesis has been used as a powerful stimulant to enhance blood vessel formation in tissue engineering scaffolds [9, 10]. However, during development, changes in the concentrations, timing, or spatial distribution of angiogenic growth factors result in vascular abnormalities [11].…”

Designing hydrogels for controlled drug delivery

“…A hydrogel releasing a drug or encapsulating drug-secreting cells is regulated as a combination product, and therefore its regulatory approval process is often longer than a scaffold without any payload. As the duration of patent protection is limited, a longer approval time can limit commercial viability 213 . The cost to develop hydrogel drug delivery systems from the bench to bedside, as for all drugs, is estimated to be quite high; drug development costs are generally estimated to run between US $50–800 million, which provides a significant impediment to commercialization 214 .…”

Inflammation, fracture and bone repair

“…Thus, there are new opportunities to “re-engineer” the current constructs by the functionalization of scaffolds and by direct cell delivery. The functionalization of scaffolds may involve controlled release of biologics to extend their bioactivity, the recruitment and differentiation of autologous stem cells, the local, temporal control of biologics, and to couple scaffold degradation with new bone growth [180, 184–186]. A more recent approach is to reproduce the sequential release of polarizing macrophage factors, that promote the classical activation into M1-macrophage during the first 24 hours (e.g.…”